Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United States.
Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for inflammatory diseases and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curcumin also downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia, atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".

Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF-kappa B, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies.

Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. Traditionally known for its an antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB. Interestingly, however, curcumin at low doses can also enhance antibody responses. This suggests that curcumin's reported beneficial effects in arthritis, allergy, asthma, atherosclerosis, heart disease, Alzheimer's disease, diabetes, and cancer might be due in part to its ability to modulate the immune system. Together, these findings warrant further consideration of curcumin as a therapy for immune disorders.

PMID: 17211725 [PubMed - indexed for MEDLINE]

Cancer Chemopreventive Effects of Curcumin
Surh YJ, Chun KS
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, South Korea. surh@plaza.snu.ac.krAdv Exp Med Biol—2007;595:149-72

Chemoprevention, which is referred to as the use of nontoxic natural or synthetic chemicals to intervene in multistage carcinogenesis, has emerged as a promising and pragmatic medical approach to reduce the risk of cancer. Numerous components of edible plants, collectively termed "phytochemicals" have been reported to possess substantial chemopreventive properties. Curcumin, a yellow coloring ingredient derived from Curcuma longa L. (Zingiberaceae), is one of the most extensively investigated and well-defined chemopreventive phytochemicals. Curcumin has been shown to protect against skin, oral, intestinal, and colon carcinogenesis and also to suppress angiogenesis and metastasis in a variety animal tumor models. It also inhibits the proliferation of cancer cells by arresting them in the various phases of the cell cycle and by inducing apoptosis. Moreover, curcumin has a capability to inhibit carcinogen bioactivation via suppression of specific cytochrome P450 isozymes, as well as to induce the activity or expression of phase II carcinogen detoxifying enzymes. Well-designed intervention studies are necessary to assess the chemopreventive efficacy of curcumin in normal individuals as well as high-risk groups. Sufficient data from pharmacodynamic as well as mechanistic studies are necessary to advocate clinical evaluation of curcumin for its chemopreventive potential.

Chemoprevention is a promising anti-cancer approach with reduced secondary effects in comparison to classical chemotherapy. Curcumin, one of the most studied chemopreventive agents, is a natural compound extracted from Curcuma longa L. that allows suppression, retardation or inversion of carcinogenesis. Curcumin is also described as an anti-tumoral, anti-oxidant and anti-inflammatory agent capable of inducing apoptosis in numerous cellular systems. In this review, we describe both properties and mode of action of curcumin on carcinogenesis, gene expression mechanisms and drug metabolism.

Curcumin, a natural component of the rhizome of curcuma longa has emerged as one of the most powerful chemopreventive and anticancer agents. Its biological effects range from antioxidant, anti-inflammatory to inhibition of angiogenesis and is also shown to possess specific antitumoral activity. The molecular mechanism of its varied cellular effects has been studied in some details and it has been shown to have multiple targets and interacting macromolecules within the cell. Curcumin has been shown to possess anti-angiogenic properties and the angioinhibitory effects of curcumin manifest due to down regulation of proangiogenic genes such as VEGF and angiopoitin and a decrease in migration and invasion of endothelial cells. One of the important factors implicated in chemoresistance and induced chemosensitivity is NFkB and curcumin has been shown to down regulate NFkB and inhibit IKB kinase thereby suppressing proliferation and inducing apoptosis. Cell lines that are resistant to certain apoptotic inducers and radiation become susceptible to apoptosis when treated in conjunction with curcumin. Besides this it can also act as a chemopreventive agent in cancers of colon, stomach and skin by suppressing colonic aberrant crypt foci formation and DNA adduct formation. This review focuses on the various aspects of curcumin as a potential drug for cancer treatment and its implications in a variety of biological and cellular processes vis-à-vis its mechanism of action.

Curcuma spp. contain turmerin, essential oils, and curcuminoids, including curcumin. Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is regarded as the most biologically active constituent of the spice turmeric and it comprises 2-8% of most turmeric preparations. Preclinical data from animal models and phase I clinical studies performed with human volunteers and patients with cancer have demonstrated low systemic bioavailability following oral dosing. Efficient first-pass metabolism and some degree of intestinal metabolism, particularly glucuronidation and sulfation of curcumin, might explain its poor systemic availability when administered via the oral route. A daily oral dose of 3.6 g of curcumin is compatible with detectable levels of the parent compound in colorectal tissue from patients with cancer. The levels demonstrated might be sufficient to exert pharmacological activity. There appears to be negligible distribution of the parent drug to hepatic tissue or other tissues beyond the gastrointestinal tract. Curcumin possesses wide-ranging anti-inflammatory and anticancer properties. Many of these biological activities can be attributed to its potent antioxidant capacity at neutral and acidic pH, its inhibition of cell signaling pathways at multiple levels, its diverse effects on cellular enzymes, and its effects on cell adhesion and angiogenesis. In particular, curcumin's ability to alter gene transcription and induce apoptosis in preclinical models advocates its potential utility in cancer chemoprevention and chemotherapy. With regard to considerable public and scientific interest in the use of phytochemicals derived from dietary components to combat or prevent human diseases, curcumin is currently a leading agent.

PMID: 17569224 [PubMed - indexed for MEDLINE]

Colon cancer prevention
Studies suggest "A daily oral dose of 3.6 g of curcumin is compatible with detectable levels of the parent compound in colorectal tissue from patients with cancer." This is equivalent to 2 capsules of JIVA Curcumin and fermented soy capsule twice a day.

The most practical approach to reduce the morbidity and mortality of cancer is to delay the process of carcinogenesis through the use of chemopreventive agents. This necessitates that safer compounds, especially those derived from natural sources must be critically examined for chemoprevention. A spice common to India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa. Pre-clinical studies in a variety of cancer cell lines including breast, cervical, colon, gastric, hepatic, leukemia, oral epithelial, ovarian, pancreatic, and prostate have consistently shown that curcumin possesses anti-cancer activity in vitro and in pre-clinical animal models. The robust activity of curcumin in colorectal cancer has led to five phase I clinical trials being completed showing the safety and tolerability of curcumin in colorectal cancer patients. To date clinical trials have not identified a maximum tolerated dose of curcumin in humans with clinical trials using doses up to 8000mg per day. The success of these trials has led to the development of phase II trials that are currently enrolling patients. Overwhelming in vitro evidence and completed clinical trials suggests that curcumin may prove to be useful for the chemoprevention of colon cancer in humans. This review will focus on describing the pre-clinical and clinical evidence of curcumin as a chemopreventive compound in colorectal cancer.

Large bowel cancer is one of the most common human malignancies in western countries, including North America. Several epidemiological studies have detected decreases in the risk of colorectal cancer in individuals who regularly use aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical trials with NSAIDs in patients with familial adenomatous polyposis have demonstrated that treatment with NSAIDs causes regression of pre-existing adenomas. Preclinical efficacy studies using realistic laboratory animal models have provided scientifically sound evidence as to how NSAIDs act to retard, block, and reverse colonic carcinogenesis. Selective COX-2 inhibitors (celecoxib) as well as naturally occurring anti-inflammatory agents (curcumin) have proven to be effective chemopreventive agents against colonic carcinogenesis. There is growing optimism for the view that realization of preventive concepts in large bowel cancer will also serve as a model for preventing malignancies of the prostate, the breast, and many other types of cancer. There is increasing interest in the use of combinations of low doses of chemopreventive agents that differ in their modes of action in order to increase their efficacy and minimize toxicity. Preclinical studies conducted in our laboratory provide strong evidence that the administration of combinations of chemopreventive agents (NSAIDs, COX-2 inhibitors, DFMO, statins) at low dosages inhibit carcinogenesis more effectively and with less toxicity than when these agents are given alone.

Turmeric, the bright yellow spice extracted from the tuberous rhizome of the plant Curcuma longa, has been used in traditional Indian and Chinese systems of medicine for centuries to treat a variety of ailments, including jaundice and hepatic disorders, rheumatism, anorexia, diabetic wounds, and menstrual difficulties. Most of the medicinal effects of turmeric have been attributed to curcumin, the principal curcumanoid found in turmeric. Recent evidence that curcumin exhibits strong anti-inflammatory and antioxidant activities and modulates the expression of transcription factors, cell cycle proteins, and signal transducing kinases has prompted the mechanism-based studies on the potential of curcumin to primarily prevent and treat cancer and inflammatory diseases. Little work has been done to study the effect of curcumin on the development of immune responses. This review discusses current knowledge on the immunomodulatory effects of curcumin on various facets of the immune response, including its effect on lymphoid cell populations, antigen presentation, humoral and cell-mediated immunity, and cytokine production.

The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilized because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.

Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.

PMID: 17999464 [PubMed - in process]

Suggested dosage for Curcumin as maintenance therapy in individuals with quiescent ulcerative colitis: 1 gram of curcumin twice a day: i.e. 2 capsules of JIVA twice a day with 1 serving JIVA Fermented soy and curcumin powdered nutraceutical beverage a day mixed/blended with 8 ounces of water/ a little soy milk with or without non-citrus fruits such as bananas, berries.

BACKGROUND & AIMS: Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC).

METHODS: Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up. RESULTS: Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P=.040). Recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (P=.049). Furthermore, curcumin improved both CAI (P=.038) and EI (P=.0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed.

CONCLUSIONS: Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.

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